Publications by authors named "Fernando P Hartwig"

36 Publications

Time-dependent decay of detectable antibodies against SARS-CoV-2: A comparison of ELISA with two batches of a lateral-flow test.

Braz J Infect Dis 2021 Jul-Aug;25(4):101601. Epub 2021 Aug 5.

Universidade Federal de Pelotas, Pelotas, RS, Brazil.

Background: Large-scale epidemiological studies of seroprevalence of antibodies against SARS-CoV-2 often rely on point-of-care tests that provide immediate results to participants. Yet, little is known on how long rapid tests remain positive after the COVID-19 episode, or how much variability exists across different brands and even among batches of the same test.

Methods: In November 2020, we assessed the sensitivity of three tests applied to 133 individuals with a previous positive PCR result between April and October. All subjects provided finger prick blood samples for two batches (A and B) of the Wondfo lateral-flow IgG/IgM test, and dried blood spot samples for the S-UFRJ ELISA test.

Results: Overall sensitivity levels were 92.5% (95% CI 86.6-96.3), 63.2% (95% CI 54.4-71.4) and 33.8% (95% CI 25.9-42.5) for the S-UFRJ test, Wondfo A and Wondfo B tests, respectively. There was no evidence of a decline in the positivity of S-UFRJ with time since the diagnosis, but the two Wondfo batches showed sharp reductions to as low as 41.9% and 19.4%, respectively, for subjects with a positive PCR in June or earlier. Positive results for batch B of the rapid test were 35% to 54% lower than for batch A at any given month of diagnosis.

Interpretation: Whereas the ELISA test showed high sensitivity and stability of results over the five months of the study, both batches of the rapid test showed substantial declines, with one of the batches consistently showing lower sensitivity levels than the other. ELISA tests based on dried-blood spots are an inexpensive alternative to rapid lateral-flow tests in large-scale epidemiological studies.

Funding: The study was funded by the "Todos Pela Saúde" initiative, Instituto Serrapilheira, Brazilian Ministry of Health, Brazilian Collective Health Association (ABRASCO) and the JBS S.A. initiative 'Fazer o Bem Faz Bem'.
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http://dx.doi.org/10.1016/j.bjid.2021.101601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339571PMC
October 2021

COVID-19 and social distancing among children and adolescents in Brazil.

Rev Saude Publica 2021 25;55:42. Epub 2021 Jun 25.

Universidade Federal de Pelotas. Faculdade de Medicina. Departamento de Medicina Social. Pelotas, RS, Brasil.

Objective: To estimate the prevalence of SARS-CoV-2 antibodies and the adherence to measures of social distancing in children and adolescents studied in three national surveys conducted in Brazil between May-June 2020.

Methods: Three national serological surveys were conducted in 133 sentinel cities located in all 27 Federative Units. Multistage probability sampling was used to select 250 individuals per city. The total sample size in age ranges 0-9 and 10-19 years old are of 4,263 and 8,024 individuals, respectively. Information on children or adolescents was gathered with a data collection app, and a rapid point-of-case test for SARS-CoV-2 was conducted on a finger prick blood sample.

Results: The adjusted prevalence of antibodies was 2.9% (2.2-3.6) among children 0-9 years, 2.2% (1.8-2.6) among adolescents 10-19 years, and 3.0% (2.7-3.3) among adults 20+years. Prevalence of antibodies was higher among poor children and adolescents compared to those of rich families. Adherence to social distancing measures was seen in 72.4% (71.9-73.8) of families with children, 60.8% (59.6-61.9) for adolescents, and 57.4% (56.9-57.8) for adults. For not leaving the house except for essential matters the proportions were 81.7% (80.5-82.9), 70.6% (69.6-61.9), and 65.1% (64.7-65.5), respectively. Among children and adolescents, social distancing was strongly associated with socioeconomic status, being much higher in the better-off families.

Conclusions: The prevalence of antibodies against SARS-CoV-2 showed comparable levels among children, adolescents, and adults. Adherence to social distancing measures was more prevalent in children, followed by adolescents. There were important socioeconomic differences in the adherence to social distancing among children and adolescents.
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http://dx.doi.org/10.11606/s1518-8787.2021055003832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225319PMC
July 2021

Slow Spread of SARS-CoV-2 in Southern Brazil Over a 6-Month Period: Report on 8 Sequential Statewide Serological Surveys Including 35 611 Participants.

Am J Public Health 2021 08 29;111(8):1542-1550. Epub 2021 Jun 29.

Pedro C. Hallal, Mariângela F. Silveira, Ana M. B. Menezes, Bernardo L. Horta, Aluísio J. D. Barros, Nadege Jacques, Luís Paulo Vidaletti, Fernando P. Hartwig, Fernando C. Barros, and Cesar G. Victora are with the Postgraduate Program in Epidemiology, Universidade Federal de Pelotas, Brazil. Lúcia C. Pellanda and Helena Schirmer are with the Universidade Federal de Ciências de Saúde de Porto Alegre, Brazil. Gabriel D. Victora is with the Laboratory of Lymphocyte Dynamics, Rockefeller University, New York, NY. Odir A. Dellagostin is with the Postgraduate Program in Biotechnology, Universidade Federal de Pelotas. Claudio J. Struchiner is with the Fundação Getúlio Vargas, Rio de Janeiro, Brazil. Marcelo N. Burattini is with the Universidade Federal de São Paulo, Brazil. Marilia A. Mesenburg is with the Postgraduate Program in Epidemiology, Universidade Federal de Pelotas, and the Universidade Federal de Ciências de Saúde de Porto Alegre. Emanuele L. Ambros is with the Secretaria Municipal de Saúde de Uruguaiana, Brazil. Evelise M. Berlezi is with the Universidade de Ijuí, Brazil. Jane D. P. Renner is with the Universidade de Santa Cruz do Sul, Brazil. Kaue Collares is with the Universidade de Passo Fundo, Brazil. Maria Letícia R. Ikeda is with the Universidade do Vale do Rio dos Sinos, Sao Leopoldo, Brazil. Thiago M. Ardenghi is with the Universidade Federal de Santa Maria, Brazil. Patricia de Gasperi is with the Universidade de Caxias do Sul, Brazil.

To evaluate the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) over 6 months in the Brazilian State of Rio Grande do Sul (population 11.3 million), based on 8 serological surveys. In each survey, 4151 participants in round 1 and 4460 participants in round 2 were randomly sampled from all state regions. We assessed presence of antibodies against SARS-CoV-2 using a validated lateral flow point-of-care test; we adjusted figures for the time-dependent decay of antibodies. The SARS-CoV-2 antibody prevalence increased from 0.03% (95% confidence interval [CI] = 0.00%, 0.34%; 1 in every 3333 individuals) in mid-April to 1.89% (95% CI = 1.36%, 2.54%; 1 in every 53 individuals) in early September. Prevalence was similar across gender and skin color categories. Older adults were less likely to be infected than younger participants. The proportion of the population who reported leaving home daily increased from 21.4% (95% CI = 20.2%, 22.7%) to 33.2% (95% CI = 31.8%, 34.5%). SARS-CoV-2 infection increased slowly during the first 6 months in the state, differently from what was observed in other Brazilian regions. Future survey rounds will continue to document the spread of the pandemic.
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http://dx.doi.org/10.2105/AJPH.2021.306351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489617PMC
August 2021

High prevalence of symptoms among Brazilian subjects with antibodies against SARS-CoV-2.

Sci Rep 2021 06 24;11(1):13279. Epub 2021 Jun 24.

Universidade Federal de Pelotas, Pelotas, Brazil.

Since the beginning of the pandemic of COVID-19, there has been a widespread assumption that most infected persons are asymptomatic. Using data from the recent wave of the EPICOVID19 study, a nationwide household-based survey including 133 cities from all states of Brazil, we estimated the proportion of people with and without antibodies for SARS-CoV-2 who were asymptomatic, which symptoms were most frequently reported, number of symptoms and the association with socio-demographic characteristics. We tested 33,205 subjects using a rapid antibody test previously validated. Information was collected before participants received the test result. Out of 849 (2.7%) participants positive for SARS-CoV-2 antibodies, only 12.1% (95% CI 10.1-14.5) reported no symptoms, compared to 42.2% (95% CI 41.7-42.8) among those negative. The largest difference between the two groups was observed for changes in smell/taste (56.5% versus 9.1%, a 6.2-fold difference). Changes in smell/taste, fever and body aches were most likely to predict positive tests as suggested by recursive partitioning tree analysis. Among individuals without any of these three symptoms, only 0.8% tested positive, compared to 18.3% of those with both fever and changes in smell or taste. Most subjects with antibodies against SARS-CoV-2 are symptomatic, even though most present only mild symptoms.
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http://dx.doi.org/10.1038/s41598-021-92775-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225900PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Patterns of Growth in Childhood in Relation to Adult Schooling Attainment and Intelligence Quotient in 6 Birth Cohorts in Low- and Middle-Income Countries: Evidence from the Consortium of Health-Oriented Research in Transitioning Societies (COHORTS).

J Nutr 2021 Aug;151(8):2342-2352

Nutrition and Health Sciences, Laney Graduate School, Emory University, Atlanta, GA, USA.

Background: Growth faltering has been associated with poor intellectual performance. The relative strengths of associations between growth in early and in later childhood remain underexplored.

Objectives: We examined the association between growth in childhood and adult human capital in 5 low- and middle-income countries (LMICs).

Methods: We analyzed data from 9503 participants in 6 prospective birth cohorts from 5 LMICs (Brazil, Guatemala, India, the Philippines, and South Africa). We used linear and quasi-Poisson regression models to assess the associations between measures of height and relative weight at 4 age intervals [birth, age ∼2 y, midchildhood (MC), adulthood] and 2 dimensions of adult human capital [schooling attainment and Intelligence Quotient (IQ)].

Results: Meta-analysis of site- and sex-specific estimates showed statistically significant associations between size at birth and height at ∼2 y and the 2 outcomes (P < 0.001). Weight and length at birth and linear growth from birth to ∼2 y of age (1 z-score difference) were positively associated with schooling attainment (β: 0.13; 95% CI: 0.08, 0.19, β: 0.17; 95% CI: 0.07, 0.32, and β: 0.25, 95% CI: 0.10, 0.40, respectively) and adult IQ (β: 0.74, 95% CI: 0.35, 1.14, β: 0.73, 95% CI: 0.35, 1.10, and β: 1.52, 95% CI: 0.96, 2.08, respectively). Linear growth from age 2 y to MC and from MC to adulthood was not associated with higher school attainment or IQ. Change in relative weight in early childhood, MC, and adulthood was not associated with either outcome.

Conclusions: Linear growth in the first 1000 d is a predictor of schooling attainment and IQ in adulthood in LMICs. Linear growth in later periods was not associated with either of these outcomes. Changes in relative weight across the life course were not associated with schooling and IQ in adulthood.
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http://dx.doi.org/10.1093/jn/nxab096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436131PMC
August 2021

Missed childhood immunizations during the COVID-19 pandemic in Brazil: Analyses of routine statistics and of a national household survey.

Vaccine 2021 06 27;39(25):3404-3409. Epub 2021 Apr 27.

Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, RS, Brazil.

Introduction: There is widespread concern that disruption to health services during the COVID-19 pandemic has led to declines in immunization coverage among young children, but there is limited information on the magnitude of such impact. High immunization coverage is essential for reducing the risk of vaccine preventable diseases.

Methods: We used data from two nationwide sources covering the whole of Brazil. Data from the Information System of the National Immunization Program (SIPNI) on the monthly number of vaccine doses administered to young children were analyzed. The second source was a survey in 133 large cities in the 27 states in the country, carried out from August 24-27. Respondents answered a question on whether children under the age of three years had missed any scheduled vaccinations during the pandemic, and available vaccination cards were photographed for later examination.

Results: SIPNI data showed that, relative to January and February 2020, there was a decline of about 20% in vaccines administered to children aged two months or older during March and April, when social distancing was at the highest level in the country. After May, vaccination levels returned to pre-pandemic values. Survey data, based on the interviews and on examination of the vaccine cards, showed that 19.0% (95% CI 17.0;21.1%) and 20.6% (95% CI 19.0;23.1%) of children, respectively, had missed immunizations. Missed doses were most common in the North (Amazon) region and least common in the South and Southeast, and also more common among children from poor than from wealthy families.

Interpretation: Our results show that the pandemic was associated with a reduction of about 20% in child vaccinations, but this was reverted in recent months. Children from poor families and from the least developed regions of the country were most affected. There is an urgent need to booster immunization activities in the country to compensate for missed doses, and to reduce geographic and socioeconomic inequalities.
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http://dx.doi.org/10.1016/j.vaccine.2021.04.046DOI Listing
June 2021

Prevalence of antibodies against SARS-CoV-2 according to socioeconomic and ethnic status in a nationwide Brazilian survey.

Rev Panam Salud Publica 2020 29;44:e135. Epub 2020 Oct 29.

Universidade Federal de Pelotas Pelotas Brazil Universidade Federal de Pelotas, Pelotas, Brazil.

Objectives: To investigate socioeconomic and ethnic group inequalities in prevalence of antibodies against SARS-CoV-2 in the 27 federative units of Brazil.

Methods: In this cross-sectional study, three household surveys were carried out on May 14-21, June 4-7, and June 21-24, 2020 in 133 Brazilian urban areas. Multi-stage sampling was used to select 250 individuals in each city to undergo a rapid antibody test. Subjects answered a questionnaire on household assets, schooling and self-reported skin color/ethnicity using the standard Brazilian classification in five categories: white, black, brown, Asian or indigenous. Principal component analyses of assets was used to classify socioeconomic position into five wealth quintiles. Poisson regression was used for the analyses.

Results: 25 025 subjects were tested in the first, 31 165 in the second, and 33 207 in the third wave of the survey, with prevalence of positive results equal to 1.4%, 2.4%, and 2.9% respectively. Individuals in the poorest quintile were 2.16 times (95% confidence interval 1.86; 2.51) more likely to test positive than those in the wealthiest quintile, and those with 12 or more years of schooling had lower prevalence than subjects with less education. Indigenous individuals had 4.71 (3.65; 6.08) times higher prevalence than whites, as did those with black or brown skin color. Adjustment for region of the country reduced the prevalence ratios according to wealth, education and ethnicity, but results remained statistically significant.

Conclusions: The prevalence of antibodies against SARS-CoV-2 in Brazil shows steep class and ethnic gradients, with lowest risks among white, educated and wealthy individuals.
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http://dx.doi.org/10.26633/RPSP.2020.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595003PMC
October 2020

Geospatial estimation of reproductive, maternal, newborn and child health indicators: a systematic review of methodological aspects of studies based on household surveys.

Int J Health Geogr 2020 10 13;19(1):41. Epub 2020 Oct 13.

International Center for Equity in Health, Universidade Federal de Pelotas, Pelotas, Brazil.

Background: Geospatial approaches are increasingly used to produce fine spatial scale estimates of reproductive, maternal, newborn and child health (RMNCH) indicators in low- and middle-income countries (LMICs). This study aims to describe important methodological aspects and specificities of geospatial approaches applied to RMNCH coverage and impact outcomes and enable non-specialist readers to critically evaluate and interpret these studies.

Methods: Two independent searches were carried out using Medline, Web of Science, Scopus, SCIELO and LILACS electronic databases. Studies based on survey data using geospatial approaches on RMNCH in LMICs were considered eligible. Studies whose outcomes were not measures of occurrence were excluded.

Results: We identified 82 studies focused on over 30 different RMNCH outcomes. Bayesian hierarchical models were the predominant modeling approach found in 62 studies. 5 × 5 km estimates were the most common resolution and the main source of information was Demographic and Health Surveys. Model validation was under reported, with the out-of-sample method being reported in only 56% of the studies and 13% of the studies did not present a single validation metric. Uncertainty assessment and reporting lacked standardization, and more than a quarter of the studies failed to report any uncertainty measure.

Conclusions: The field of geospatial estimation focused on RMNCH outcomes is clearly expanding. However, despite the adoption of a standardized conceptual modeling framework for generating finer spatial scale estimates, methodological aspects such as model validation and uncertainty demand further attention as they are both essential in assisting the reader to evaluate the estimates that are being presented.
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http://dx.doi.org/10.1186/s12942-020-00239-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552506PMC
October 2020

SARS-CoV-2 antibody prevalence in Brazil: results from two successive nationwide serological household surveys.

Lancet Glob Health 2020 11 23;8(11):e1390-e1398. Epub 2020 Sep 23.

Postgraduate Programme in Epidemiology, Universidade Federal de Pelotas, Pelotas, Brazil. Electronic address:

Background: Population-based data on COVID-19 are essential for guiding policies. There are few such studies, particularly from low or middle-income countries. Brazil is currently a hotspot for COVID-19 globally. We aimed to investigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody prevalence by city and according to sex, age, ethnicity group, and socioeconomic status, and compare seroprevalence estimates with official statistics on deaths and cases.

Methods: In this repeated cross-sectional study, we did two seroprevalence surveys in 133 sentinel cities in all Brazilian states. We randomly selected households and randomly selected one individual from all household members. We excluded children younger than 1 year. Presence of antibodies against SARS-CoV-2 was assessed using a lateral flow point-of-care test, the WONDFO SARS-CoV-2 Antibody Test (Wondfo Biotech, Guangzhou, China), using two drops of blood from finger prick samples. This lateral-flow assay detects IgG and IgM isotypes that are specific to the SARS-CoV-2 receptor binding domain of the spike protein. Participants also answered short questionnaires on sociodemographic information (sex, age, education, ethnicity, household size, and household assets) and compliance with physical distancing measures.

Findings: We included 25 025 participants in the first survey (May 14-21) and 31 165 in the second (June 4-7). For the 83 (62%) cities with sample sizes of more than 200 participants in both surveys, the pooled seroprevalence increased from 1·9% (95% CI 1·7-2·1) to 3·1% (2·8-3·4). City-level prevalence ranged from 0% to 25·4% in both surveys. 11 (69%) of 16 cities with prevalence above 2·0% in the first survey were located in a stretch along a 2000 km of the Amazon river in the northern region. In the second survey, we found 34 cities with prevalence above 2·0%, which included the same 11 Amazon cities plus 14 from the northeast region, where prevalence was increasing rapidly. Prevalence levels were lower in the south and centre-west, and intermediate in the southeast, where the highest level was found in Rio de Janeiro (7·5% [4·2-12·2]). In the second survey, prevalence was similar in men and women, but an increased prevalence was observed in participants aged 20-59 years and those living in crowded conditions (4·4% [3·5-5·6] for those living with households with six or more people). Prevalence among Indigenous people was 6·4% (4·1-9·4) compared with 1·4% (1·2-1·7) among White people. Prevalence in the poorest socioeconomic quintile was 3·7% (3·2-4·3) compared with 1·7% (1·4-2·2) in the wealthiest quintile.

Interpretation: Antibody prevalence was highly heterogeneous by country region, with rapid initial escalation in Brazil's north and northeast. Prevalence is strongly associated with Indigenous ancestry and low socioeconomic status. These population subgroups are unlikely to be protected if the policy response to the pandemic by the national government continues to downplay scientific evidence.

Funding: Brazilian Ministry of Health, Instituto Serrapilheira, Brazilian Collective Health Association, and the JBS Fazer o Bem Faz Bem.
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http://dx.doi.org/10.1016/S2214-109X(20)30387-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511212PMC
November 2020

[Age structure and mortality due to COVID-19].

Cien Saude Colet 2020 09 28;25(9):3691. Epub 2020 Aug 28.

Universidade Federal de Pelotas, Pelotas, RS, Brazil.

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http://dx.doi.org/10.1590/1413-81232020259.21182020DOI Listing
September 2020

Guidelines for performing Mendelian randomization investigations.

Wellcome Open Res 2019 28;4:186. Epub 2020 Apr 28.

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.

This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into nine sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust statistical methods and one on other approaches), data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 18 months.
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http://dx.doi.org/10.12688/wellcomeopenres.15555.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384151PMC
April 2020

Population-based surveys of antibodies against SARS-CoV-2 in Southern Brazil.

Nat Med 2020 08 8;26(8):1196-1199. Epub 2020 Jul 8.

Universidade Federal de Pelotas, Pelotas, Brazil.

Population-based data on COVID-19 are urgently needed. We report on three rounds of probability sample household surveys in the state of Rio Grande do Sul (Brazil), carried out in nine large municipalities using the Wondfo lateral flow point-of-care test for immunoglobulin M and G antibodies against SARS-CoV-2 (https://en.wondfo.com.cn/product/wondfo-sars-cov-2-antibody-test-lateral-flow-method-2/). Before survey use, the assay underwent four validation studies with pooled estimates of sensitivity (84.8%; 95% confidence interval (CI) = 81.4-87.8%) and specificity (99.0%; 95% CI = 97.8-99.7%). We calculated that the seroprevalence was 0.048% (2/4,151; 95% CI = 0.006-0.174) on 11-13 April (round 1), 0.135% (6/4,460; 95% CI = 0.049-0.293%) on 25-27 April (round 2) and 0.222% (10/4,500; 95% CI = 0.107-0.408) on 9-11 May (round 3), with a significant upward trend over the course of the surveys. Of 37 family members of positive individuals, 17 (35%) were also positive. The epidemic is at an early stage in the state, and there is high compliance with social distancing, unlike in other parts of Brazil. Periodic survey rounds will continue to monitor trends until at least the end of September, and our population-based data will inform decisions on preventive policies and health system preparedness at the state level.
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http://dx.doi.org/10.1038/s41591-020-0992-3DOI Listing
August 2020

Trends in the prevalence of COVID-19 infection in Rio Grande do Sul, Brazil: repeated serological surveys.

Cien Saude Colet 2020 Jun 14;25(suppl 1):2395-2401. Epub 2020 Apr 14.

Programa de Pós-Graduação em Epidemiologia, Universidade Federal de Pelotas. R. Marechal Deodoro 1160, Centro. 96020-220 Pelotas RS Brasil.

COVID-19, the disease produced by the virus SARS-CoV-2, has spread quickly throughout the world, leading the World Health Organization to first classify it as an international health emergency and, subsequently, declaring it pandemic. The number of confirmed cases, as April 11, surpassed 1,700,000, but this figure does not reflect the prevalence of COVID-19 in the population as, in many countries, tests are almost exclusively performed in people with symptoms, particularly severe cases. To properly assess the magnitude of the problem and to contribute to the design of evidence-based policies for fighting COVID-19, one must accurately estimate the population prevalence of infection. Our study is aimed at estimating the prevalence of infected individuals in the state of Rio Grande do Sul, Brazil, to document how fast the infection spreads, and to estimate the proportion of infected persons who present or presented symptoms, as well as the proportion of asymptomatic infections. Four repeated serological surveys will be conducted in probability samples of nine sentinel cities every two weeks. Tests will be performed in 4,500 participants in each survey, totaling18,000 interviews. Interviews and tests will be conducted at the participants' household. A rapid test for the detection of antibodies will be used; the test was validated prior to the beginning of the fieldwork.
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http://dx.doi.org/10.1590/1413-81232020256.1.09632020DOI Listing
June 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 06 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

The median and the mode as robust meta-analysis estimators in the presence of small-study effects and outliers.

Res Synth Methods 2020 May 10;11(3):397-412. Epub 2020 Mar 10.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Meta-analyses based on systematic literature reviews are commonly used to obtain a quantitative summary of the available evidence on a given topic. However, the reliability of any meta-analysis is constrained by that of its constituent studies. One major limitation is the possibility of small-study effects, when estimates from smaller and larger studies differ systematically. Small-study effects may result from reporting biases (ie, publication bias), from inadequacies of the included studies that are related to study size, or from reasons unrelated to bias. We propose two estimators based on the median and mode to increase the reliability of findings in a meta-analysis by mitigating the influence of small-study effects. By re-examining data from published meta-analyses and by conducting a simulation study, we show that these estimators offer robustness to a range of plausible bias mechanisms, without making explicit modelling assumptions. They are also robust to outlying studies without explicitly removing such studies from the analysis. When meta-analyses are suspected to be at risk of bias because of small-study effects, we recommend reporting the mean, median and modal pooled estimates.
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http://dx.doi.org/10.1002/jrsm.1402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359861PMC
May 2020

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Hum Mol Genet 2019 08;28(15):2615-2633

Icelandic Heart Association, Kopavogur, Iceland.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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http://dx.doi.org/10.1093/hmg/ddz070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644157PMC
August 2019

Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.

PLoS One 2019 10;14(5):e0216222. Epub 2019 May 10.

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Background: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

Methods And Findings: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

Conclusions: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216222PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510421PMC
January 2020

Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.

Nat Genet 2019 04 29;51(4):636-648. Epub 2019 Mar 29.

Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
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http://dx.doi.org/10.1038/s41588-019-0378-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467258PMC
April 2019

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.

Am J Epidemiol 2019 06;188(6):1033-1054

Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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http://dx.doi.org/10.1093/aje/kwz005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545280PMC
June 2019

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Nat Commun 2019 01 22;10(1):376. Epub 2019 Jan 22.

Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, 01246903, SP, Brazil.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
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http://dx.doi.org/10.1038/s41467-018-08008-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342931PMC
January 2019

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.

Am J Hum Genet 2019 01 27;104(1):112-138. Epub 2018 Dec 27.

School of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323610PMC
January 2019

Breastfeeding and intelligence in adulthood: due to genetic confounding?

Lancet Glob Health 2018 12;6(12):e1276-e1277

Post-Graduate Program in Epidemiology- Universidade Federal de Pelotas, Pelotas 96020-220, Brazil.

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http://dx.doi.org/10.1016/S2214-109X(18)30371-1DOI Listing
December 2018

Genome-wide burden and association analyses implicate copy number variations in asthma risk among children and young adults from Latin America.

Sci Rep 2018 09 27;8(1):14475. Epub 2018 Sep 27.

Institute of Collective Health, Federal University of Bahia, 40110-040, Salvador, Bahia, Brazil.

The genetic architecture of asthma was relatively well explored. However, some work remains in the field to improve our understanding on asthma genetics, especially in non-Caucasian populations and with regards to commonly neglected genetic variants, such as Copy Number Variations (CNVs). In the present study, we investigated the contribution of CNVs on asthma risk among Latin Americans. CNVs were inferred from SNP genotyping data. Genome wide burden and association analyses were conducted to evaluate the impact of CNVs on asthma outcome. We found no significant difference in the numbers of CNVs between asthmatics and non-asthmatics. Nevertheless, we found that CNVs are larger in patients then in healthy controls and that CNVs from cases intersect significantly more genes and regulatory elements. We also found that a deletion at 6p22.1 is associated with asthma symptoms in children from Salvador (Brazil) and in young adults from Pelotas (Brazil). To support our results, we conducted an in silico functional analysis and found that this deletion spans several regulatory elements, including two promoter elements active in lung cells. In conclusion, we found robust evidence that CNVs could contribute for asthma susceptibility. These results uncover a new perspective on the influence of genetic factors modulating asthma risk.
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http://dx.doi.org/10.1038/s41598-018-32837-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160443PMC
September 2018

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

PLoS One 2018 18;13(6):e0198166. Epub 2018 Jun 18.

Icelandic Heart Association, Kopavogur, Iceland.

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198166PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005576PMC
January 2019

Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis.

Nat Genet 2018 04 20;50(4):549-558. Epub 2018 Mar 20.

Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.

Osteoarthritis is a common complex disease imposing a large public-health burden. Here, we performed a genome-wide association study for osteoarthritis, using data across 16.5 million variants from the UK Biobank resource. After performing replication and meta-analysis in up to 30,727 cases and 297,191 controls, we identified nine new osteoarthritis loci, in all of which the most likely causal variant was noncoding. For three loci, we detected association with biologically relevant radiographic endophenotypes, and in five signals we identified genes that were differentially expressed in degraded compared with intact articular cartilage from patients with osteoarthritis. We established causal effects on osteoarthritis for higher body mass index but not for triglyceride levels or genetic predisposition to type 2 diabetes.
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http://dx.doi.org/10.1038/s41588-018-0079-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896734PMC
April 2018

Breastfeeding moderates FTO related adiposity: a birth cohort study with 30 years of follow-up.

Sci Rep 2018 02 7;8(1):2530. Epub 2018 Feb 7.

Universidade Católica de Pelotas, Pelotas, Rio Grande do Sul, Brazil.

This study assessed the association of breastfeeding with body composition at 30 years, among subjects who have been prospectively followed since birth in a southern Brazilian city. We also evaluated whether breastfeeding moderated the association between the rs9939609 variant in the FTO gene and adiposity. At 30 years, total and predominant breastfeeding were positively associated with lean mass index and inversely with visceral fat thickness. Among subjects breastfed for <1 month, all outcomes showed monotonically increasing values with additional copies of the A allele in the FTO genotype (rs9939609). Associations among subjects breastfed for one month or longer tended to be in the same direction but showed lower magnitude and were less consistent; for all outcomes. Interactions had p values ≤ 0.05 for body mass index, fat mass index and waist circumference. Even among young adults, breastfeeding moderates the association between the FTO variant rs9939609 and body composition.
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http://dx.doi.org/10.1038/s41598-018-20939-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803210PMC
February 2018

A Genome-Wide Association Study in Hispanics/Latinos Identifies Novel Signals for Lung Function. The Hispanic Community Health Study/Study of Latinos.

Am J Respir Crit Care Med 2018 07;198(2):208-219

1 Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.

Rationale: Lung function and chronic obstructive pulmonary disease (COPD) are heritable traits. Genome-wide association studies (GWAS) have identified numerous pulmonary function and COPD loci, primarily in cohorts of European ancestry.

Objectives: Perform a GWAS of COPD phenotypes in Hispanic/Latino populations to identify loci not previously detected in European populations.

Methods: GWAS of lung function and COPD in Hispanic/Latino participants from a population-based cohort. We performed replication studies of novel loci in independent studies.

Measurements And Main Results: Among 11,822 Hispanic/Latino participants, we identified eight novel signals; three replicated in independent populations of European Ancestry. A novel locus for FEV in ZSWIM7 (rs4791658; P = 4.99 × 10) replicated. A rare variant (minor allele frequency = 0.002) in HAL (rs145174011) was associated with FEV/FVC (P = 9.59 × 10) in a region previously identified for COPD-related phenotypes; it remained significant in conditional analyses but did not replicate. Admixture mapping identified a novel region, with a variant in AGMO (rs41331850), associated with Amerindian ancestry and FEV, which replicated. A novel locus for FEV identified among ever smokers (rs291231; P = 1.92 × 10) approached statistical significance for replication in admixed populations of African ancestry, and a novel SNP for COPD in PDZD2 (rs7709630; P = 1.56 × 10) regionally replicated. In addition, loci previously identified for lung function in European samples were associated in Hispanic/Latino participants in the Hispanic Community Health Study/Study of Latinos at the genome-wide significance level.

Conclusions: We identified novel signals for lung function and COPD in a Hispanic/Latino cohort. Including admixed populations when performing genetic studies may identify variants contributing to genetic etiologies of COPD.
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http://dx.doi.org/10.1164/rccm.201707-1493OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058984PMC
July 2018

Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Am J Hum Genet 2018 01;102(1):88-102

MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.
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http://dx.doi.org/10.1016/j.ajhg.2017.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777980PMC
January 2018
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